Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac/R) have revolutionized psychiatry. However, a major problem with SSRIs is a 2-3 week delay in therapeutic onset. Studies from the last funding period indicate that SSRIs produce a robust desensitization of hypothalamic post-synaptic serotonin lA (5-HT1A) receptors in rats. This desensitization has a gradual onset (7-14 days), corresponding with the 2-3 week delay in therapeutic effects of SSRIs. Hence, desensitization of post-synaptic 5-HTIA receptors could be a model of some of the therapeutic effects of SSRIs. The long delay in clinical improvement after the onset of SSRI treatment remains a fundamental problem that may be overcome by a more comprehensive understanding of the underlying basis for 5-HT1A receptor desensitization. Therefore this competitive renewal will focus on the mechanisms responsible for the homologous desensitization of post-synaptic hypothalamic 5-HTIA receptor systems during treatment of rats with SSRIs, The focus of this proposal is on the 5-HT1A receptor - Gz protein - mitogen-activated protein kinase (MAPK also known as ERK1/2) cascade. The MAP kinase cascade (Raf-MEK-ERK) is involved in many cellular processes including receptor desensitization. Our preliminary studies indicate that 5-HT1A-receptor activation produces a rapid phosphorylation of MAP kinase (ERK1/2) in the rat hypothalamic paraventricular nucleus. Our central hypothesis is that Gz protein-MAP kinase signaling mediates the desensitization of 5-HTIA receptors by SSRIs. Four specific aims are proposed: Specific Aim 1 will test the hypothesis that Gz proteins mediate the 5-HTIA receptor-mediated activation of MAP kinase signaling in the hypothalamus. Specific Aim 2 will test the hypothesis that reduced expression of Gz proteins mediates SSRI-induced desensitization of hypothalamic 5-HTIA receptors. Specific Aim 3 will test the hypothesis that MAP kinase signaling mediates the SSRI-induced desensitization of post-synaptic 5-HTIA receptors in the hypothalamus. Specific Aim 4 will identify the transcription factors (c-myc and Spl) that mediate fluoxetine-induced desensitization of 5-HTIA receptors. The proposed studies will provide an in-depth understanding of the regulation of post-synaptic 5-HTIA receptor signaling in vivo and will identify new targets for the treatment of mood disorders.